Esters and derivatives of formula I:
where R1 and R2 are independently chosen alkyl of one to three carbons and R3 is alkyl of 1 to 8 carbon atoms, and alternatively compounds of formula Ia:
wherein R1 and R2 are independently chosen from alkyl of one to three carbons or phenyl, or R1 and R2 are taken together as —(CH2)n— wherein n is 4 or 5, and R is alkyl of 1 to 8 carbon atoms, are important intermediates in the preparation of compounds useful as anti-hypercholesterolemic agents having an inhibitory effect on HMG-COA reductase. Such agents include atorvastatin, cerivastatin, pitavastatin, fluvastatin and rosuvastatin.
Compounds of formula Ib:
wherein R1 and R2 are alkyl of 1 to 5 carbons, and R3 is as defined above, are also useful as intermediates in the preparation of said anti-hypercholesterolemic agents.
EP 0 319 847 describes a process for the preparation of compounds of formula I starting from L-malic acid. This process, however, suffers from the fact that the process is not industrially scalable and also possesses purification problems due to the non-crystalline nature of the intermediates.
U.S. Pat. No. 5,399,722 describes a process for preparing such compounds starting from commercially available ethyl ω-cloroacetoacetate or its benzyloxy derivative. The disadvantages of this process are that a stereo-selective reduction using a costly ruthenium-BINAP catalyst is employed and the desired compound of formula I is obtained in six steps.
U.S. Pat. No. 5,481,009 describes a five-step process for preparing such compounds starting from 4-phenyl-3-butenoic acid. The process uses both expensive materials such as N,O-dimethyl hydroxylamine and hazardous steps (ozonolysis) to obtain the desired product.
U.S. Pat. No. 5,998,633 describes a process for the preparation of protected esters of 3,4-dihydroxy butyric acid from a carbohydrate moiety which is transformed into the desired 3,4-dihydroxy butanoic acid derivatives in about 4 steps. The 3,4-dihydroxy butanoic acid derivative is then functionalized into compounds of formula I involving a multiple number of steps.
U.S. Pat. No. 6,140,527 describes a process for producing butyric acid derivatives starting from a butene derivative followed by reaction with a reagent capable of adding across the double bond. However, this procedure necessitates the need for a resolution step.
EP 0 104 750 describes a process for the preparation of 5-hydroxy-3-oxo pentanoic acid derivatives by alkylation of 3-hydroxybutyrate derivatives. The products of this process are racemic thus necessitating a resolution step.
The objective of the present invention is to provide a simple and industrially scalable process for the preparation of derivatives of formula I starting from commercially available and inexpensive materials.